This invention concerns the use of isotype-specific retinoic acid receptor (RAR) agonists for the inhibition of alveolar destruction and/or to promote the formation of alveoli in mammalian lung tissue deficient in adequate numbers of functional alveoli.
Among aerobic animals, the lung functions to provide an interface for the exchange of gases between blood and the atmosphere. The agents of this exchange are numerous small sacs termed alveoli (in adult humans about 300,000,000 per lung) that provide a gas permeable-liquid impermeable barrier between the gas and liquid phases. Between the alveoli are numerous capillaries carrying deoxygenated blood to the lung from the tissues and oxygenated blood from the alveoli to the tissues. The partial pressure of oxygen in the lungs is. approximately. 100 mm Hg at sea level; at this pressure the binding of oxygen by hemoglobin in the erythrocytes is favored. The alveoli thus provide a means for presenting the oxygen to hemoglobin to permit the conversion of deoxyhemoglobin to hemoglobin. Because the exchange occurs at the surface of the gas/blood barrier, alveoli have evolved as a means for providing extremely high surface area in a compact overall area, thus maximizing possible gas exchange. Lack of adequate gas exchange would lead to disability, which could progress to death.
Diseases that result in fewer alveoli therefore are quite serious, and are common causes of inadequate oxygenation and resultant disability and death. Among such diseases are bnrochiopulmonary dysplasia (BPD) and emphysema. BPD is a disease of prematurely born infants, and is characterized mainly by a failure of the infant to form a sufficient number of appropriately-sized alveoli. Emphysema, a disease of middle and advanced age, appears to be due to progressive proteinase-induced alveolar destruction.
The process of alveoli formation is reasonably well understood from a gross developmental standpoint, and seems to be similar in rat, mouse, and human, the major species studied. The process includes the subdivision (septation) of the saccules that constitute the gas-exchange region of the immature lung. Septation results in the formation of smaller, more numerous gas-exchange structures (alveoli). The timing of the onset and cessation of septation vary among species, but both onset and cessation are critical to the formation of alveoli of the size and number needed for adequate oxygenation.
The molecular basis of the initiation and cessation of alveoli formation are not as well understood as the structural events and timing accompanying alveoli development. Knowledge of the molecular signals that initiate and end septation, and that govern the spacing of septa relative to the O2-demand, are virtually unknown; however, several lines of evidence suggest that certain retinoids (retinoic acid and its derivatives) may play a key signaling role. In Massaro et al., Nature Medicine 3:675 (1997), hereby incorporated by reference herein, rats were treated with elastase, causing destruction of alveolar walls in a manner similar to that seen in emphysema. Treatment of the rats with all-trans-retinoic acid (ATRA), an agonist of all RAR isotypes, appeared to reverse this destruction. Similarly, treatment of newborn rats (which are born with immature lungs lacking an adult complement of alveoli) with ATRA induced the formation of an increased number of alveoli in rats without enlarging the lung. See Massaro et al., Am. J. Physiol. 270: L305 (1996) incorporated by reference herein.
ATRA can have a multiplicity of physiological effects. The retinoid receptors, when bound by an appropriate ligand, are mediators of various life processes, including reproduction, metabolism, differentiation, hematopoiesis, and embryogenesis.
There is therefore a need for methods and compositions that provide a practicable means for inhibiting alveolar destruction and/or promoting the formation of alveoli in a postnatal aerobic animal, particularly a mammal such as a human. Additionally, there is a need for therapeutic methods that are able to more specifically treat such a condition without a high likelihood of serious side effects.